Atorvastatin treatment is effective when used in combination with mefloquine in an experimental cerebral malaria murine model

<p>Abstract</p> <p>Background</p> <p>One of the major complications of <it>Plasmodium falciparum </it>infection is cerebral malaria (CM), which causes one million deaths worldwide each year, results in long-term neurological sequelae and the treatment for which is only partially effective. Statins are recognized to have an immunomodulatory action, attenuate sepsis and have a neuroprotective effect. Atorvastatin (AVA) has shown in vitro anti-malarial activity and has improved the activity of mefloquine (MQ) and quinine.</p> <p>Methods</p> <p>The efficiency of 40 mg/kg intraperitoneal AVA, alone or in association with MQ, was assessed in an experimental <it>Plasmodium berghei </it>ANKA rodent parasite model of CM and performed according to different therapeutic schemes. The effects on experimental CM were assessed through the evaluation of brain histopathological changes and neuronal apoptosis by TUNEL staining.</p> <p>Results</p> <p>AVA alone in the therapeutic scheme show no effect on survival, but the prophylactic scheme employing AVA associated with MQ, rather than MQ alone, led to a significant delay in mouse death and had an effect on the onset of CM symptoms and on the level of parasitaemia. Histopathological findings show a correlation between brain lesions and CM onset. A neuronal anti-apoptotic effect of AVA in the AVA + MQ combination was not shown.</p> <p>Conclusions</p> <p>The combination of AVA and MQ therapy led to a significant delay in mouse mortality. There were differences in the incidence, time to cerebral malaria and the level of parasitaemia when the drug combination was administered to mice. When used in combination with MQ, AVA had a relevant effect on the in vivo growth inhibition and clinical outcome of <it>P. berghei </it>ANKA-infected mice.</p

Malar J

BACKGROUND: Resistance to all available anti-malarial drugs has emerged and spread including artemisinin derivatives and their partner drugs. Several genes involved in artemisinin and partner drugs resistance, such as pfcrt, pfmdr1, pfK13 or pfpm2, have been identified. However, these genes do not properly explain anti-malarial drug resistance, and more particularly clinical failures observed in Africa. Mutations in genes encoding for Plasmodium falciparum proteins, such as P. falciparum Acetyl-CoA transporter (PfACT), P. falciparum UDP-galactose transporter (PfUGT) and P. falciparum cyclic amine resistance locus (PfCARL) have recently been associated to resistance to imidazolopiperazines and other unrelated drugs. METHODS: Mutations on pfugt, pfact and pfcarl were characterized on 86 isolates collected in Dakar, Senegal and 173 samples collected from patients hospitalized in France after a travel in African countries from 2015 and 2016 to assess their potential association with ex vivo susceptibility to chloroquine, quinine, lumefantrine, monodesethylamodiaquine, mefloquine, dihydroartemisinin, artesunate, doxycycline, pyronaridine and piperaquine. RESULTS: No mutations were found on the genes pfugt and pfact. None of the pfcarl described mutations were identified in these samples from Africa. The K784N mutation was found in one sample and the K734M mutation was identified on 7.9% of all samples for pfcarl. The only significant differences in ex vivo susceptibility according to the K734M mutation were observed for pyronaridine for African isolates from imported malaria and for doxycycline for Senegalese parasites. CONCLUSION: No evidence was found of involvement of these genes in reduced susceptibility to standard anti-malarial drugs in African P. falciparum isolates

PROVEBLUE, METHYLENE BLUE, AS AN ANTIMALARIAL DRUG

66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Baltimore, MD, NOV 05-09, 2017International audienc

PROVEBLUE, METHYLENE BLUE, AS AN ANTIMALARIAL DRUG

66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Baltimore, MD, NOV 05-09, 2017International audienc

ABSENCE OF ASSOCIATION BETWEEN EX VIVO SUSCEPTIBILITY TO PIPERAQUINE AND POLYMORPHISMS IN EXONUCLEASE GENE AND COPY NUMBERS IN PLASMEPSIN 2 GENE IN AFRICAN PLASMODIUM FALCIPARUM ISOLATES

66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Baltimore, MD, NOV 05-09, 2017International audienc

ABSENCE OF ASSOCIATION BETWEEN EX VIVO SUSCEPTIBILITY TO PIPERAQUINE AND POLYMORPHISMS IN EXONUCLEASE GENE AND COPY NUMBERS IN PLASMEPSIN 2 GENE IN AFRICAN PLASMODIUM FALCIPARUM ISOLATES

66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Baltimore, MD, NOV 05-09, 2017International audienc

Synthesis, Anti-Plasmodial Activities, and Mechanistic Insights of 4-Aminoquinoline-Triazolopyrimidine Hybrids

International audienc

Prevalence of Mutations in the pfcoronin Gene and Association with Ex Vivo Susceptibility to Common Quinoline Drugs against Plasmodium falciparum

International audienceBackground: Artemisinin-based combination therapy (ACT) was recommended to treat uncomplicated falciparum malaria. Unlike the situation in Asia where resistance to ACT has been reported, artemisinin resistance has not yet emerged in Africa. However, some rare failures with ACT or patients continuing to be parasitaemic on day 3 after ACT treatment have been reported in Africa or in travellers returning from Africa. Three mutations (G50E, R100K, and E107V) in the pfcoronin gene could be responsible for artemisinin resistance in Africa. Methods: The aims of this study were first to determine the prevalence of mutations in the pfcoronin gene in African P. falciparum isolates by Sanger sequencing, by targeting the 874 samples collected from patients hospitalised in France after returning from endemic areas in Africa between 2018 and 2019, and secondly to evaluate their association with in vitro reduced susceptibility to standard quinoline antimalarial drugs, including chloroquine, quinine, mefloquine, desethylamodiaquine, lumefantrine, piperaquine, and pyronaridine. Results: The three mutations in the pfcoronin gene (50E, 100K, and 107V) were not detected in the 874 P. falciparum isolates. Current data show that another polymorphism (P76S) is present in many countries of West Africa (mean prevalence of 20.7%) and Central Africa (11.9%) and, rarely, in East Africa (4.2%). This mutation does not appear to be predictive of in vitro reduced susceptibility to quinolines, including artemisinin derivative partners in ACT such as amodiaquine, lumefantrine, piperaquine, pyronaridine, and mefloquine. Another mutation (V62M) was identified at low prevalence (overall prevalence of 1%). Conclusions: The 76S mutation is present in many African countries with a prevalence above 10%. It is reassuring that this mutation does not confer in vitro resistance to ACT partners

Synthesis and antiplasmodial evaluation of 1H-1,2,3-triazole grafted 4-aminoquinoline-benzoxaborole hybrids and benzoxaborole analogues

International audienc